Compounds which inhibit cytosolic phospholipase A2 have been disclosed in U.S. patent application Ser. No. 10/302,636 filed Nov. 22, 2002, the disclosure of which is incorporated by reference herein. These compounds are useful for a variety of pharmaceutical purposes, including the relief of pain and inflammation. In order to bring a pharmaceutical compound to market, it is necessary to have an economically feasible process for making the compound. Often, a process that works in the laboratory is not practical from a commercial standpoint. It would be desirable to have a relatively inexpensive and efficient method for making at least some of the aforesaid compounds.
A process disclosed in U.S. patent application Ser. No. 10/302,636 for making 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid may be summarized as follows: methyl-4-iodobenzoate is reacted with allyl alcohol to provide 4-(3-Oxo-propyl)-benzoic acid methyl ester, which is then reacted with 5-chloro-2-methylindole to yield 4-[3-(5-chloro-2-methylindol-3-yl)propyl]benzoic acid methyl ester; this product is reacted with benzhydryl bromide to produce 4-[3-(1-benzhydryl-5-chloro-2-methylindol-3-yl)propyl]benzoic acid methyl ester, which is then reacted with benzoyl peroxide to produce the 2-formyl indole; the 2 formyl indole is then reacted with nitromethane followed by Zn(Hg)/HCl to form the 2-(2-aminoethyl) indole; this amine is then reacted with [(3,4-dichlorophenyl)-methyl]sulfonyl chloride to produce 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid methyl ester, which is then hydrolyzed to form 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid. In this process, chromatography is used to separate some of the compounds made in the aforesaid reactions. It would be desirable to have a process for making the product that does not require the use of chromatography.
Appleton, et al., in Tetrahedron Lett. 1993, 34, 1529, teach reductive C-3 alkylation of 3-unsubstituted indoles to produce C-3 functionalized indoles, especially 3-(arylmethyl)indoles and 3-(heteroarylmethyl)indoles. In the reference reaction, the initial indole is reacted with an aldehyde or ketone using triethylsilane and trifluoroacetic acid.
A method for synthesizing N-but-3-ynylphthalimide is taught by Hoffmann, et al., J. Med. Chem., 18(3), 278-284 (1975). In this method, phthalic acid anhydride is reacted with 4-amino-1-butyne in glacial acetic acid to produce the target compound.
Ezquerra, et al., in J. Org. Chem. 1998, 61, 5804-5812, disclose methods for making substituted indoles starting from aromatic amines. For example, they disclose that a 2,4-substituted aniline may be reacted with bis(pyridine)iodonium(1) tetrafluoroborate to create a 2-iodo-4,6-substituted aniline in high yield. The iodoaniline may be reacted with HC≡CS(Me)3 followed by CuI in DMF to form a 5,7-substituted indole.
Xiao, et al., J. Org. Chem., 64, 9646-9652 (1999), have described a preparation for 2-iodoaniline in which a 4-substituted aniline is reacted with iodine in an aqueous sodium bicarbonate solution. The authors also describe using 2-iodoaniline in the synthesis of other compounds.
Pierce, et al., in J. Org. Chem. 1998, 63, 8536, disclose a method for making N-benzyl anilines.
Villemin and Goussu, in Hetereocycles 1989, 29, 1255, disclose a method and conditions for the cyclization of 2-acetyleno-anilines.